Recent studies have indicated that cytochrome P450 (CYP) metabolites of arachidonic acid (AA), in particular 20-HETE, play a central role in the regulation of renal tubular and vascular function and the long-term control of arterial pressure. During the last funding period, this investigator identified a gene of the cytochrome P4504A family that is differentially expressed in the kidney of Dahl S and Lewis rats and that cosegregates with the development of hypertension in an F2 cross of Dahl S and Lewis rats. To further explore the role of this system in the control of renal function, they have developed (in collaboration with Dr. J. Rapp) congenic strains of rats in which overlapping segments of chromosome 5 of the Lewis rat, that include or exclude the P4504A region, have been introgressed into the Dahl S genetic background by greater than 8 generation of selective back-cross breedings. They now propose to determine whether the P4504A genes play a causal role on altering renal function and/or the development of hypertension and glomerulosclerosis in Dahl S rats by: 1) comparing blood pressure, renal function and the expression of P4504A enzymes in congenic strains of rats in which the P4504A alleles of normotensive Lewis rats have been introgressed into the Dahl S genetic background; 2) determining whether selective intrarenal blockade of the formation of 20-HETE can """"""""rescue"""""""" the hypertensive and renal phenotypes in P4504A congenic Dahl S rats; 3) cloning and sequencing the 5'-flanking regions of the P4504A2 and 4A3 genes to determine whether there are sequence variants that can explain the differences in the expression of these genes in the outer medullas of the kidneys of Dahl S and Lewis rats. These studies will provide important new information regarding the role of P450 metabolites of AA in the regulation of renal function and will determine whether this pathway plays a primary or secondary role in the development of hypertension and/or glomerular disease in Dahl S rats.
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